Researchers at Oregon State University have discovered one of the reasons why broccoli may be good for your health. They found that sulforaphane, a dietary compound from broccoli that’s known to help prevent prostate cancer, may work through its influence on long, non-coding RNAs. This is another step forward in a compelling new area of study on the underlying genetics of cancer development and progression. The findings were published by researchers from Oregon State University in the Journal of Nutritional Biochemistry.
The research provides more evidence for how these lncRNAs, which were once thought to be a type of “junk DNA” of no particular value or function, may instead play a critical role in triggering cells to become malignant and spread. Growing evidence shows that lncRNAs, which number in the thousands, have a major role in cell biology and development, often by controlling what genes are turned on, or “expressed” to carry out their genetic function. Scientists now believe that when these lncRNAs are dysregulated (uncontrolled) they can contribute to multiple disease processes, including cancer. The lncRNAs are also of special interest, researchers say, because they are so highly cell- and tissue-specific.
Unlike many chemotherapeutic drugs that affect healthy cells as well as malignant ones and can cause undesired side effects, the control of lncRNAs may offer a new way to specifically prevent or slow the progression of malignant cells. “This could be a turning point in our understanding of how cancer may be triggered and spreads,” said Emily Ho, the endowed director of the Moore Family Center for Whole Grain Foods, Nutrition and Preventive Health at OSU, a professor in the College of Public Health and Human Sciences and principal investigator with the Linus Pauling Institute. “It’s obviously of interest that this dietary compound, found at some of its highest levels in broccoli, can affect lncRNAs. This could open the door to a whole range of new dietary strategies, foods or drugs that might play a role in cancer suppression or therapeutic control.” For more information, see the following link.
It is a good idea to add cruciferous veggies to your diet. However, while cruciferous extracts from broccoli, kale, cabbage etc. containing small amounts of sulforaphane are commercially available as supplements, it should be noted that the amounts of sulforaphane needed for activity against prostate cancer in men is not known and usually requires considerable amounts of the extract or vegetable to be ingested. Therefore, before taking any extracts, please consult with your health provider.
The Prostate Cancer Foundation published a fairly comprehensive yet concise e mail resource describing various facets of prostate cancer beginning with early screening and detection. The reader is urged to spend some time perusing this article. There is so much information here that I am simply linking the article at this point. The initial portion of the article deals with screening and biopsy.
A section entitled “For Patients- Recently Diagnosed? Read This Section First,” describes finding a doctor and treatment center, treatment options, side effects, clinical trials, financial resources, guides and even videos. Information by stage is also provided which includes information on screening, detection and diagnosis, active surveillance, recurrence and advanced disease. A section entitled “Understanding Prostate Cancer” describes risk factors, symptoms and prevention among others.
Men with low-risk prostate cancer have similar recurrence-free survival rates when treated with surgical robotic prostatectomy or brachytherapy, but those who received surgery had fewer urinary or sexual problems two years after treatment, a randomized trial in Italy has concluded. The study was recently published in the April 2017 issue of the Canadian Journal of Urology [Claudio et al, 24 (2), 8728-8733].
Treatment of early-stage or low-risk prostate cancer relies on active surveillance, surgery or radiation therapy. In particular, both robot-assisted radical prostatectomy (RARP) and brachytherapy (BP) — a type of internal radiation therapy in which radioactive seeds are placed inside or near a tumor — have been shown to effectively treat prostate cancer. However, until now little was known about their long-term effects. “Treatment decisions that men with low-risk prostate cancer have to make can be difficult, as a lot of it depends on what the patient is looking for and what type of experience their physician has to offer,” said Dr. David Samadi, chairman of urology and chief of robotic surgery at New York’s Lenox Hill Hospital
Italian researchers at Milan’s San Paolo Hospital conducted the single-center, prospective study from January 2012 to January 2016 to compare the outcomes of 165 patients randomly assigned to receive either RARP or BT. They followed all patients for up to two years after treatment, including clinical evaluation and determination of prostate-specific antigen (PSA) levels.
Researchers also evaluated urinary and erectile functions, and found that overall biochemical recurrence-free survival rates were similar among the two groups. Patients undergoing RARP had a 97.4 percent recurrence-free survival rate, compared to 96.1 percent reported in the BT-treated group. Biochemical recurrence is the term used when a patient’s PSA levels start rising again. “This was actually expected,” said Dr. Samadi. “A two-year follow-up is a short period of time to ascertain much difference between the two procedures.”
While the recurrence-free survival was similar in both groups, researchers saw different outcomes when analyzing sexual or urinary symptoms. Men undergoing BT regained continence faster than those who received RARP during the first six months of follow-up. But this difference was no longer significant after 12 months and 24 months. Interestingly, men in the BT group had more urinary symptoms during the two-year follow-up.
Regarding sexual function, both groups showed a decreased ability to maintain an erection right after treatment. However, RARP-treated men recovered potency much more quickly than their BP-treated counterparts. By the final follow-up, 90 percent of RARP-treated men were back to normal, compared to only 60 percent of men in the BT group. “These are factors any doctor and the men they see with low-risk prostate cancer need to take into consideration when making any treatment decision,” Dr. Samadi said. “When they make the comparison between RARP and BT, RARP clearly shows the upper hand in treating prostate cancer effectively and managing symptoms better at this stage.”
It must be noted that these results may vary somewhat with the experience of the medical personnel involved and should be discussed with one’s physician if applicable.
Collaborative-therapy: White American pelicans wintering in Florida Everglades; photo: BJ Gabrielsen;
Having advanced prostate cancer albeit at an early stage, I, in discussions with my Florida oncologist, had decided to pursue a course of immunotherapy first before using drugs that kill the cancer cells directly. I remembered writing previous website blogs in which several prominent oncologists and urologists recommended treating the cancer with immunotherapies first. I recently completed the three treatments comprising PROVENGE (sipuleucel-T) and recently posted a blog about the entire experience.
Meanwhile, I still keep in touch with former friends and colleagues at the National Cancer Institute (NCI) – National Institutes of Health (NIH) in Frederick and Bethesda, MD. Within a day or two of completing PROVENGE®, I received an email from an NCI friend describing a new NCI clinical trial in Bethesda, MD to determine the safety and efficacy of PROSTVAC (an NCI-discovered vaccine), coupled with two antibody therapies, nivolumab (OPDIVO®) and ipilimumab (Yervoy®), already approved for treating other cancers. The trial is recruiting two kinds of patients; men with localized prostate cancer who have elected radical prostatectomy and men like myself with advanced disease progressing on hormonal therapy. PROSTVAC is a cancer vaccine in that helps the immune system recognize and attack cancer cells, while ipilimumab (Yervoy) and nivolumab (OPDIVO) block certain mechanisms and signals within the body that prevent the immune system from attacking cancer cells. For specific trial information, see this link.
PROSTVAC is in late stage Phase III development (Prospect trial) for metastatic, hormone-resistant prostate cancer patients who are either asymptomatic or minimally symptomatic. It is a therapeutic pox virus cancer vaccine directed at PSA-producing cells. It is administered with or without GM-CSF (granulocyte macrophage colony-stimulating factor, a protein secreted by immune system cells that functions as a white blood cell growth factor. PROSTVAC immunotherapy (administered by s.c. injections) is intended to trigger a specific and targeted immune response against prostate cancer cells and tissue by using virus-based immunotherapies that carry the tumor-associated antigen PSA (prostate-specific antigen) along with 3 natural human immune-enhancing costimulatory molecules collectively designated as TRICOM (LFA-3, ICAM-1, and B7.1 When PSA-TRICOM is presented to the immune system in PROSTVAC, cytotoxic T lymphocytes (CTLs) are generated that may recognize and kill PSA-expressing cancer cells.
Nivolumab (OPDIVO®), is used as a first line treatment for inoperable or metastatic melanoma in combination with ipilumumab and as a second-line treatment for squamous non-small cell lung tumors and as a second-line treatment for renal cell carcinoma. It is a human IgG4 anti-PD-1 monoclonal antibody. Nivolumab works as a checkpoint inhibitor, blocking a signal that would have prevented activated T-cells from attacking the cancer, thus allowing the immune system to clear the cancer. PD-1 is a protein on the surface of activated T cells. If another molecule, called programmed cell death 1 ligand 1 or programmed cell death 1 ligand 2 (PD-L1 or PD-L2), binds to PD-1, the T cell becomes inactive. This is one way that the body regulates the immune system, to avoid an overreaction. Many cancer cells make PD-L1, which inhibits T cells from attacking the tumor. Thus, nivolumab blocks PD-L1 from binding to PD-1, allowing the T cell to work.
Ipilimumab (also known as MDX-101 and MDX-010 and marketed as Yervoy) is a human monoclonal antibody developed by Bristol-Myers-Squibb and approved for the treatment of melanoma. As a single agent, it failed in clinical trials in metastatic, hormone-refractory prostate cancer. However it may work better in combination therapy. It works by activating a patient’s own immune system by causing cytotoxic T-lymphocytes to potentially combat tumor cells. Specifically, it targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), preventing the antigen from interacting with its ligands and thereby activating the patient’s own immune system by causing these T-cells to potentially combat tumor cells. More simply, Yervoy blocks a switch that turns off an anti-tumor cellular response. Therefore, Yervoy is an agent that “blocks a blocker” thereby aiding the immune system to fight the tumor. The bad news however is that prostate cancer responds to Yervoy by increasing the expression of two other immune checkpoint molecules, PD-L1 and VISTA. And both send a “don’t-eat-me signal” to immune cells. That reaction is why Yervoy, by itself, offers little patient benefit.
Enzalutamide (Xtandi®) and abiraterone acetate (Zytiga®) are two approved hormone therapies commonly prescribed for men with hormone-resistant advanced prostate cancer. They block the androgen receptor signaling that is essential to the cancer’s growth. Although they represent breakthroughs in metastatic treatment, 20 to 40 percent of patients fail to respond to them. These men with advanced prostate cancer have an abnormal version of a prostate cancer protein that binds with testosterone. The protein is missing a key connector that binds to abiraterone and enzalutamide. The abnormal protein is caused by a genetic variant called AR-V7. Johns Hopkins researchers discovered that the variation, which lacks a portion of the full androgen receptor, was associated with resistance to abiraterone and enzalutamide. The drugs failed to block androgen receptor signaling, thus allowing prostate cancer cells to keep growing. Most patients who test positive for AR-V7 get limited or no benefit from abiraterone or enzalutamide. Conversely, Johns Hopkins researchers discovered that prostate cancer patients who lacked the AR-V7 androgen receptor variation survive longer than those with the variation. The initial study, “AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer” was published in the New England Journal of Medicine in 2014. A test for the genetic variant, AR-V7 was described further in this website’s October 13th, 2015 post.
An article in the April 24th, Prostate Cancer News Today, stated that Qiagen will begin marketing the test that Johns Hopkins University developed. If doctors know that a prostate cancer patient is resistant to the drugs, they can develop a more tailored treatment. The test, called AdnaTest Prostate Cancer Panel AR-V7, will detect that resistance. The test is called a liquid biopsy because it examines circulating tumor cells (CTC’s) in blood instead of tissue. It shows whether cancer cells in a blood sample have the AR-V7 variation.
In addition to the test being used in treatment, researchers can use it to help select patients for clinical trials. In a recent study, thirty-one men received Zytiga and 31 Xtandi. The results were clear. The PSA response rate was zero in patients with the AR-V7 variant. In other words, none of the patients with the variant responded to the drugs. In contrast, 54% of patients who lacked the variant responded to Zytiga, and 68% to Xtandi. Overall survival rates of patients with the variant were 5.5 months with Zytiga and 10.6 months with Xtandi. Patients without the variation survived beyond the duration of the study.
QIAGEN is working with several pharmaceutical companies on trying the test in prostate cancer clinical trials. They plan to make the AdnaTest kit commercially available this year.
